The primary objective of this project is to increase understanding of the mechanisms by which several sulfur containing compounds inhibit chemical carcinogenesis. Disulfiram exhibits a broad spectrum of anticarcinogenic effects. Two structurally related compounds, diethyldithiocarbamate and bis (ethylxanthogen), also inhibit the tumor producing effects of chemical carcinogens. These compounds are known to inhibit oxidative steps in the activation of certain carcinogens. Little is known about their effects on enzymes involved in non-oxidative metabolism of carcinogens. Thus, it is proposed to examine the effects of the administration of these compounds to rodents on the hepatic and extrahepatic activity profiles of several classes of enzymes which together have a major role in the non-oxidative metabolism of a wide variety of reactive electrophiles. The enzymes to be studied are glutathione S-transferases, UDP-glucuronosyltransferase, NAD(P)H:quinone reductase, and BTA-glucuronidase. The effects of benzylisothiocyanate, another anticarcinogenic sulfur compound, on the hepatic and extrahepatic activities of these enzymes will also be examined. The mechanisms by which test compounds modulate the activities of these enzymes will be explored. Studies on glutathione S-transferases will include immunoquantitation of enzyme protein and comparisons of activity of hepatic mRNA for athe major protein of this family, in untreated mice and those receiving the test compounds. The possibility that disulfiram and benzylisothiocyanate may have antithyroid activity will be evaluated in relation to the abilities of these compounds to elevate glutathione S-transferase and quinone reductase activities. Comparative studies on the modulation of enzyme profiles by disulfiram, diethyldithiocarbamate, bis(ethylxanthogen), and benzylisothiocyanate may provide information concerning the molecular properties required for specific effects on enzymes, and may aid in identifying common features in the mechanisms by which these and other compounds protect against chemical carcinogenesis. Increased understanding of the mechanisms of protection should facilitate the development or identification of safer, more potent, and more specific agents for inhibition of chemical carcinogenesis.